NM_002691.4(POLD1):c.1772_1773del (p.Lys591fs) AND Colorectal cancer, susceptibility to, 10

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 2, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV003640576.1

Allele description [Variation Report for NM_002691.4(POLD1):c.1772_1773del (p.Lys591fs)]

NM_002691.4(POLD1):c.1772_1773del (p.Lys591fs)

Gene:

POLD1:DNA polymerase delta 1, catalytic subunit [Gene - OMIM - HGNC]

Variant type:

Deletion

Cytogenetic location:

19q13.33

Genomic location:

Preferred name:

NM_002691.4(POLD1):c.1772_1773del (p.Lys591fs)

HGVS:

NC_000019.10:g.50407412_50407413del
NG_033800.1:g.28090_28091del
NM_001256849.1:c.1772_1773del
NM_001308632.1:c.1772_1773del
NM_002691.4:c.1772_1773delMANE SELECT
NP_001243778.1:p.Lys591fs
NP_001295561.1:p.Lys591fs
NP_002682.2:p.Lys591fs
LRG_785t1:c.1772_1773del
LRG_785t2:c.1772_1773del
LRG_785:g.28090_28091del
LRG_785p1:p.Lys591fs
LRG_785p2:p.Lys591fs
NC_000019.9:g.50910668_50910669del
NC_000019.9:g.50910669_50910670del
NR_046402.2:n.1817_1818del

Protein change:

K591fs

Molecular consequence:

NM_001256849.1:c.1772_1773del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001308632.1:c.1772_1773del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_002691.4:c.1772_1773del - frameshift variant - [Sequence Ontology: SO:0001589]
NR_046402.2:n.1817_1818del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Colorectal cancer, susceptibility to, 10
Synonyms:: COLORECTAL CANCER, SUSCEPTIBILITY TO, ON CHROMOSOME 19q; Colorectal cancer 10
Identifiers:: MONDO: MONDO:0012953; MedGen: C2675481; Orphanet: 220460; OMIM: 612591

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV004462564	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 2, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 23263490, 23447401, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004462564

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 2, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas.

Palles C, Cazier JB, Howarth KM, Domingo E, Jones AM, Broderick P, Kemp Z, Spain SL, Guarino E, Salguero I, Sherborne A, Chubb D, Carvajal-Carmona LG, Ma Y, Kaur K, Dobbins S, Barclay E, Gorman M, Martin L, Kovac MB, Humphray S; CORGI Consortium.; et al.

Nat Genet. 2013 Feb;45(2):136-44. doi: 10.1038/ng.2503. Epub 2012 Dec 23. Erratum in: Nat Genet. 2013 Jun;45(6):713. Guarino Almeida, Estrella [corrected to Guarino, Estrella].

PubMed [citation]

PMID:: 23263490
PMCID:: PMC3785128

Germline and somatic polymerase ε and δ mutations define a new class of hypermutated colorectal and endometrial cancers.

Briggs S, Tomlinson I.

J Pathol. 2013 Jun;230(2):148-53. doi: 10.1002/path.4185.

PubMed [citation]

PMID:: 23447401
PMCID:: PMC3709119

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004462564.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with POLD1-related conditions. This variant is not present in population databases (gnomAD no frequency). Missense variants that disrupt the 3'-5' exonuclease (proof-reading) activity of the POLD1 protein are associated with PPAP (polymerase proofreading‚Äìassociated polyposis) (PMID: 23263490, 23447401). However, loss-of-function variants that result in an absent or severely disrupted POLD1 protein, and missense variants outside the exonuclease domain, are unlikely to be associated with PPAP. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in POLD1 cause disease.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 28, 2024

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